Therapeutic Class Overview Benign Prostatic Hyperplasia Agents
INTRODUCTION Benign prostatic hyperplasia (BPH) is a histologic diagnosis that refers to the proliferation of smooth muscle and epithelial cells of the prostate. A different but related term is benign prostatic enlargement, which is used when the prostate has an increased size (McVary et al 2011). BPH causes bladder outlet obstruction that leads to lower urinary tract symptoms (LUTS). The obstruction is caused by 2 main factors: ○ A static, structural component due to the bulk of the enlarged prostate impinging upon the urethra ○ A dynamic, reversible component due to the tension of smooth muscle in the prostate (McVary et al 2011). LUTS include storage and voiding symptoms (Cunningham et al 2017a, McVary et al 2011). ○ Storage symptoms may include increased frequency of daytime urination, nocturia, urgency, and urinary incontinence. ○ Voiding symptoms may include a slow urinary stream, splitting or spraying of the urinary stream, intermittent urinary stream, hesitancy, straining to void, and terminal dribbling. The exact etiology of BPH is unknown (McVary et al 2011). Increased age is a major risk factor; the prevalence of BPH is 8% in men 31 to 40 years of age, 40 to 50% in men 51 to 60 years of age, and over 80% in men older than 80 years of age (Cunningham et al 2017b). The primary goals of treatment are to alleviate bothersome LUTS secondary to prostate enlargement, to alter the disease progression, and to prevent complications associated with BPH and LUTS (McVary et al 2011). Current treatment options include watchful waiting, surgical interventions, and pharmacological therapies (McVary et al 2011). ○ Watchful waiting is the preferred management strategy for men with mild symptoms and for those with moderate to severe symptoms who are not bothered by their LUTS. ○ Surgical and minimally invasive therapies, such as transurethral resection of the prostate and transurethral microwave thermotherapy, are recognized as the most effective strategies for BPH management. Surgical therapy is an appropriate treatment alternative for patients with moderate-to-severe LUTS and for patients who have developed acute urinary retention or other complications. ○ Pharmacological therapies are appropriate for less frequent and severe symptom management. These therapies may include alpha (α)1-adrenergic blocking agents, five-alpha (5-α)-reductase inhibitors, anticholinergic agents, and phosphodiesterase-5 (PDE5) inhibitors. This review focuses on the pharmacological agents that are Food and Drug Administration (FDA)-approved for the management of BPH and include the following drug classes: ○ α1-adrenergic blocking agents: Cardura (doxazosin), Cardura XL (doxazosin extended-release), Flomax (tamsulosin), Hytrin (terazosin), Rapaflo (silodosin), and Uroxatral (alfuzosin) . Doxazosin and terazosin are non-uroselective α1-adrenergic blocking agents. They cause relaxation in both the prostatic and vascular smooth muscles and are therefore associated with a higher incidence of orthostatic hypotension. Both agents are FDA-approved for the management of BPH and hypertension. . Cardura XL, an extended-release tablet, is only indicated for the management of BPH. . Tamsulosin, silodosin, and alfuzosin are uroselective α1-adrenergic blocking agents and are therefore associated with a lower risk of orthostatic hypotension. They are FDA-approved for the management of BPH. . Minipress (prazosin) is also included in this review since it is an α1-adrenergic blocking agent that could be used for the management of BPH, but it is only FDA-approved for the treatment of hypertension. ○ 5-α-reductase inhibitors: Avodart (dutasteride) and Proscar (finasteride) . Both agents are indicated for the treatment of BPH in men with enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and reduce the risk of BPH-related surgery. Finasteride is also indicated in combination with doxazosin to reduce the risk of symptomatic progression of BPH, and dutasteride is indicated in combination with tamsulosin for the treatment of symptomatic BPH in men with an enlarged prostate. Data as of February 13, 2018 SS-U/MG-U/ALS Page 1 of 10 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions.
Therapeutic Class Overview Benign Prostatic Hyperplasia Agents
○ PDE5 inhibitor: Cialis (tadalafil) . In addition to the management of BPH symptoms in men with or without concomitant erectile dysfunction, Cialis is FDA-approved for the treatment of erectile dysfunction. ○ Combination product: Jalyn (dutasteride/tamsulosin) is indicated for the treatment of symptomatic BPH in men with an enlarged prostate. Currently, doxazosin, prazosin, tamsulosin, terazosin, finasteride, dutasteride, alfuzosin, and the combination product dutasteride/tamsulosin are available generically. The brand product for Hytrin is no longer marketed; the product is only available generically. Medispan Therapeutic Class: Prostatic Hypertrophy Agents (tadalafil is classified with “Impotence Agents” but is also approved for BPH. Terazosin and doxazosin are classified with “antiadrenergic antihypertensives” but are also approved for BPH).
Table 1. Medications Included Within Class Review Drug Generic Availability Single Entity Agents: α1-Adrenergic Blocking Agents Cardura (doxazosin) Cardura XL (doxazosin extended-release) - Flomax (tamsulosin) Hytrin (terazosin)† Minipress (prazosin) Rapaflo (silodosin) -* Uroxatral (alfuzosin) Single Entity Agents: 5-α-Reductase Inhibitors Avodart (dutasteride) Proscar (finasteride) Single Entity Agents: PDE5 Inhibitors Cialis (tadalafil) - Combination Product Jalyn (dutasteride/tamsulosin) *A generic product is listed in the FDA Orange Book but is not currently marketed. †Brand product no longer marketed; product only available generically (Drugs@FDA 2018, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations 2018)
INDICATIONS Table 2a. Food and Drug Administration Approved Indications Cardura XL Cardura (doxazosin Flomax Minipress Hytrin Rapaflo Uroxatral Indication (doxazosin) extended- (tamsulosin) (prazosin) (terazosin) (silodosin) (alfuzosin) release) Treatment of signs and symptoms of BPH Treatment of hypertension (Prescribing Information: Cardura 2016, Cardura XL 2017, Flomax 2017, Minipress 2016, Terazosin 2014, Rapaflo 2017, Uroxatral 2015)
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making medical decisions.
Table 2b. FDA-Approved Indications: 5-α-Reductase Inhibitors Indication Avodart (dutasteride) Proscar* (finasteride) Treatment of symptomatic BPH in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention, and to reduce the risk of need for BPH-related surgery Treatment of symptomatic BPH in men with enlarged prostate in combination with tamsulosin Reduction of the risk of symptomatic progression of BPH in combination with doxazosin *If finasteride is used with Cialis to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of Cialis decreases from 4 weeks until 26 weeks, and the incremental benefit of Cialis beyond 26 weeks is unknown. (Prescribing information: Avodart 2014, Proscar 2013)
Table 2c. FDA-Approved Indications: PDE5 Inhibitors Indication Cialis* (tadalafil) Treatment of erectile dysfunction Treatment of signs and symptoms of BPH Treatment of signs and symptoms of BPH and erectile dysfunction *If Cialis is used with finasteride to initiate BPH treatment, such use is recommended for up to 26 weeks because the incremental benefit of Cialis decreases from 4 weeks until 26 weeks, and the incremental benefit of Cialis beyond 26 weeks is unknown. (Cialis prescribing information 2017)
Table 2d. FDA Approved Indications: Combination Product Jalyn Indication (dutasteride/tamsulosin) Treatment of symptomatic BPH in men with enlarged prostate (Jalyn prescribing information 2017)
Information on indications, mechanism of action, pharmacokinetics, dosing, and safety has been obtained from the prescribing information for the individual products, except where noted otherwise.
CLINICAL EFFICACY SUMMARY Alpha-Adrenergic Blocking Agents Overall, doxazosin, Cardura XL, tamsulosin, terazosin, silodosin, and alfuzosin have been shown in clinical trials to decrease International Prostate Symptom Score (IPSS) and improve LUTS in men with BPH (Chang et al 2010, Choo et al 2014, Demir et al 2009, Kawabe et al 2006, Kojima et al 2012, Leungwattanakij et al 2010, Marks et al 2013, Matsukawa et al 2009, Permpongkosol et al 2011, Ren et al 2010, Song et al 2011, Sun et al 2010, Sun et al 2011, Yamanishi et al 2010, Yokoyama et al 2011). Although some studies showed small differences among agents on selected efficacy endpoints, most randomized controlled trials and reviews demonstrated very similar efficacy among products. A meta-analysis of α1-adrenergic blocking agents (doxazosin, tamsulosin, terazosin, and alfuzosin) in men with LUTS secondary to benign prostatic obstruction did not identify any difference among agents in improving total urinary symptom scores or maximum urinary flow rate. However, tamsulosin and alfuzosin were better tolerated than doxazosin and terazosin (Djavan et al 1999). A systematic review of studies comparing alfuzosin to doxazosin and tamsulosin showed that doxazosin was associated with the greatest improvement in IPSS (MacDonald et al 2005).
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Cardura XL was associated with greater improvement in IPSS compared to tamsulosin in 2 randomized controlled trials (Chung et al 2011, Kirby et al 2003a); however, 2 other randomized controlled trials showed no difference between the 2 agents in the improvement in IPSS, nocturia, or quality of life (Xue et al 2007, Zhang et al 2011). Other head-to-head studies comparing the various α1-adrenergic blocking agents have demonstrated no difference among these agents in the improvement of BPH symptoms (Kaplan et al 1995, Kaplan et al 1997, Karadag et al 2011, Kirby et al 2001, Lapitan et al 2005, Rahardjo et al 2006, Samli et al 2004, Tsai et al 2007). Results from a meta-analysis and 2 crossover studies demonstrated that the efficacy of silodosin was similar to tamsulosin in improving IPSS and maximum urinary flow rate (Cui et al 2012, Miyakita et al 2010, Shirakawa et al 2013, Watanabe et al 2011). A 2017 Cochrane review reported the efficacy of silodosin is similar to other α1-adrenergic blockers (tamsulosin and alfuzosin), but it is associated with a higher rate of sexual adverse effects (Jung et al 2017). Another meta-analysis examined combination therapy with an anticholinergic medication (eg, tolterodine, oxybutynin ER, solifenacin, fesoterodine) plus an α1-adrenergic blocker (eg, doxazosin, tamsulosin) versus α1-adrenergic blocker monotherapy in men with BPH. Study results demonstrated the addition of an anticholinergic to an α1-adrenergic blocker slightly reduced storage symptoms and urinary frequency; however, this combination may increase the risk of acute urinary retention (Filson et al 2013). A systematic review of 48 studies concluded that older α1-adrenergic blocking agents had similar outcomes as newer α1- adrenergic blocking agents, PDE5 inhibitors, antimuscarinics, and combination therapy with agents from more than one medication class. However, older α1-adrenergic blocking agents had more adverse events than comparators (Dahm et al 2017). 5-α-Reductase Inhibitors Dutasteride has been shown to reduce prostate volume in men with BPH (Na et al 2012, Page et al 2011). Dutasteride has also been demonstrated to reduce the incidence of clinical progression of BPH compared to placebo in men with enlarged prostates (Toren et al 2013). In a Cochrane review, finasteride improved total BPH symptom scores compared to placebo (Tacklind et al 2010). One clinical study also showed that finasteride reduced the risk of clinical progression of BPH compared to placebo in men with large prostate volume (Kaplan et al 2011). The Enlarged Prostate International Comparator Study (N = 1630) showed that there was no significant difference between dutasteride and finasteride in reducing prostate volume and improving LUTS and maximum urinary flow rate in men with BPH over a period of 12 months (Nickel et al 2011). A smaller head-to-head study and a meta-analysis of 4 studies showed similar results (Jun et al 2017, Ravish et al 2007). A network meta-analysis of 21 studies found that dutasteride may improve BPH symptoms but not urinary flow or prostate volume compared to finasteride (Yin et al 2017). When compared to α1-adrenergic blocking agents, finasteride was shown in one study to be comparable to tamsulosin in improving LUTS; however, improvements were seen earlier with tamsulosin compared to finasteride (Lee 2002). Combination Therapy with an α1-Adrenergic Blocking Agent Plus a 5-α Reductase Inhibitor In men with an enlarged prostate, combination therapy may lead to improved symptom control compared to monotherapy with either an α1-adrenergic blocking agent or a 5-α reductase inhibitor (Kaplan et al 2006). However, available data are inconsistent in this area, with another study demonstrating symptom control with combination therapy to be no better than with α1-adrenergic blocking monotherapy (Kirby et al 2003b). In the 4-year, double-blind, randomized, parallel-group study known as the Combination of Avodart and Tamsulosin (CombAT) trial (N = 4844), Jalyn significantly reduced the risk of acute urinary retention or BPH-related surgery compared to tamsulosin monotherapy and demonstrated significantly greater symptom benefit (Roehrborn et al 2010). Jalyn was also associated with greater reduction in voiding and storage symptoms compared to dutasteride or tamsulosin monotherapy (Becher et al 2009). The 2-year, open-label CONDUCT trial compared Jalyn to watchful waiting with the addition of tamsulosin if symptoms did not improve in treatment-naïve men with moderately symptomatic BPH. Jalyn was shown to significantly improve the rate of clinical progression, health-related quality of life, and IPSS scores compared to the watchful waiting/tamsulosin group (Roehrborn et al 2015). PDE5 Inhibitors A meta-analysis showed that PDE5 inhibitors (Cialis, Levitra [vardenafil], and Viagra [sildenafil]) were safe and effective in improving IPSS and LUTS secondary to BPH. However, no statistically significant difference was detected in maximum urine flow rate (Qmax) or postvoid residual urine volume (Gacci et al 2016).
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making medical decisions.
Several clinical studies have also demonstrated the efficacy of Cialis in improving LUTS secondary to BPH in men with or without concomitant erectile dysfunction (Broderick et al 2010, Dmochowski et al 2013, Donatucci et al 2011, Egerdie et al 2012, Goldfischer et al 2012, Oelke et al 2012, Porst et al 2011, Roehrborn et al 2008, Takahashi et al 2018). A meta-analysis of 13 clinical studies also confirmed the efficacy of Cialis in improving LUTS associated with BPH and treating erectile dysfunction over 12 weeks (Wang et al 2018).
Combination Therapy with a PDE5 Inhibitor A randomized, double-blind trial showed combination therapy with a 5-α reductase inhibitor, finasteride, combined with the PDE5 inhibitor, Cialis, was associated with modest improvements in urinary symptoms and significantly improved patient, but not clinician, global impression of improvement when compared with finasteride monotherapy (Casabe et al 2014). A meta-analysis demonstrated that combination therapy with a PDE5 inhibitor and an α1-adrenergic blocking agent statistically significantly improved IPSS, international index of erectile function (IIEF) score, and Qmax compared to an α1- adrenergic blocking agent alone (Gacci et al 2012). A randomized controlled trial with a primary objective of evaluating the occurrence of dizziness when tadalafil was added to α1-adrenergic blocking therapy demonstrated that changes in hemodynamic signs and symptoms were similar for tadalafil- and placebo-treated patients. There was a trend toward increased hemodynamic signs and symptoms in men treated with concomitant tadalafil and non-uroselective α1-adrenergic blocking agents. Notably, this study did not demonstrate increased effectiveness with the combination therapy compared to α1-adrenergic blocking agent monotherapy, with an IPSS reduction of 2.2 in the tadalafil group and 1.33 in the placebo group (p = 0.13) (Goldfischer et al 2012).
CLINICAL GUIDELINES The American Urological Association guideline has noted no differences in efficacy among doxazosin, tamsulosin, terazosin and alfuzosin in the management of BPH (McVary et al 2011). The European Association of Urology guideline notes that all α1-adrenergic blocking agents have similar efficacy at appropriate doses (Gravas et al 2017). The American Urological Association guideline notes that there is no evidence to suggest that the clinical efficacy of 5-α reductase inhibitors differs when used for the appropriate indication (McVary et al 2011). Similarly, the European Association of Urology guideline notes that available evidence indicates that dutasteride and finasteride are equally effective in the treatment of LUTS (Gravas et al 2017). The American Urological Association guideline currently does not have a recommendation for the place in therapy for PDE5 inhibitors (McVary et al 2011); however, the European Association of Urology guideline suggests that PDE5 inhibitors are effective for reducing moderate-to-severe LUTS symptoms (Gravas et al 2017).
SAFETY SUMMARY
Alpha (α)1-adrenergic blocking agents: ○ Use of α1-adrenergic blocking agents may lead to intraoperative floppy iris syndrome during cataract and glaucoma surgery and warrant modification in surgical techniques as needed. ○ Orthostatic hypotension may occur with all agents, but is more common with doxazosin, prazosin and terazosin, especially after the first dose. ○ Doxazosin, prazosin, and Cardura XL are contraindicated in patients with hypersensitivity to quinazolines (eg, prazosin, terazosin). ○ Use of α1-adrenergic blocking agents has been associated with priapism. Patients must be advised about the seriousness of this condition. ○ Tamsulosin may cause serious allergic reactions in patients allergic to sulfa. ○ Silodosin and alfuzosin are contraindicated in patients with severe hepatic impairment and in those who are taking strong cytochrome P450 (CYP) 3A4 inhibitors. Tamsulosin also should not be used with strong CYP3A4 inhibitors. ○ Silodosin is contraindicated in patients with creatinine clearance of less than 30 mL/minute. Silodosin may also increase the risk of QT prolongation. Silodosin should not be used with concurrent strong inhibitors of P-glycoprotein. Five-alpha (5-α)-reductase inhibitors:
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○ Dutasteride and finasteride are contraindicated in women who are pregnant or have child-bearing potential; these agents should also be avoided in pediatric patients. ○ These agents may increase the risk of high-grade prostate cancer. Since these agents can decrease plasma prostate specific antigen (PSA) levels, a new PSA baseline should be obtained after at least 3 months of therapy and used for monitoring of prostate cancer. ○ Blood donation should be avoided during and for at least 6 months after therapy discontinuation.
PDE5 inhibitors: ○ Cialis is contraindicated with regular or intermittent use of any form of organic nitrates. Cialis should not be used in patients using a guanylate cyclase inhibitor, such as riociguat. ○ Cialis may cause vasodilation and should be used with caution with alcohol and avoided in patients with preexisting cardiac conditions. ○ The lowest PDE5 inhibitor dose should be used when starting therapy with concurrent α1-adrenergic blocking agents due to the risk of additive hypotension, although the manufacturer of Cialis recommends against its use with concurrent α1-adrenergic blocking agents for the treatment of BPH. ○ Patients should be advised to stop Cialis and seek immediate medical attention if they experience sudden hearing or vision loss, which could be a sign of nonarteritic anterior ischemic optic neuropathy (NAION). In patients with a history of NAION, Cialis should be used only if benefits outweigh the risks.
DOSING AND ADMINISTRATION Table 3. Dosing and Administration Available Usual Recommended Drug Route Comments Formulations Frequency Single Entity Agents: a1-Adrenergic Blocking Agents Cardura (doxazosin) Tablets Oral Daily Not recommended in severe hepatic impairment. Use with caution and monitor Cardura XL (doxazosin Tablets Oral Daily blood pressure for hypotensive symptoms extended-release) (extended- in mild or moderate hepatic impairment. release) Minipress (prazosin) Capsules Oral Twice daily Flomax (tamsulosin) Capsule Oral Daily Should be taken 30 minutes following the same meal each day. Hytrin (terazosin) Capsules Oral Daily at bedtime Dosage adjustment may be required in hepatic impairment. Rapaflo (silodosin) Capsules Oral Daily Contraindicated in severe renal and/or hepatic impairment. Dosage adjustment required in moderate renal impairment. Uroxatral (alfuzosin) Tablet Oral Daily Contraindicated in moderate to severe (extended- hepatic impairment. release) Use with caution in severe renal impairment. Single Entity Agents – 5-α-Reductase Inhibitors Avodart (dutasteride) Capsule Oral Daily Pregnancy Category X*† Proscar (finasteride) Tablet Oral Daily Pregnancy Category X*† Use with caution in hepatic impairment. Single Entity Agents – PDE5 Inhibitors Cialis (tadalafil) Tablets Oral Daily Dosage adjustment may be required in renal and/or hepatic impairment.
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making medical decisions.
Available Usual Recommended Drug Route Comments Formulations Frequency Combination Product Jalyn Capsule Oral Daily Pregnancy Category X*† (dutasteride/tamsulosin) Should be taken 30 minutes following the same meal each day. *Pregnancy Category X = contraindicated in pregnant women due to evidence of fetal abnormalities from adverse effects data from investigational or marketing experience. Risks of use of the drug in pregnant women clearly outweigh potential benefits. †Not indicated for use in women. See the current prescribing information for full details.
CONCLUSION BPH contributes to LUTS such as increased frequency of urination, nocturia, urinary hesitancy, and weak urinary streams (Cunningham et al 2017a, McVary et al 2011). Current treatment options include watchful waiting, surgical interventions and pharmacological therapies (McVary et al 2011). Alpha1-adrenergic blocking agents are the most widely used agents for the management of BPH (McVary et al 2011). ○ Cardura (doxazosin), Minipress (prazosin), and Hytrin (terazosin) are non-uroselective and are associated with a higher risk of orthostatic hypotension; therefore, therapy should be started at the lowest possible dose and titrated to the maximally tolerated dose. ○ Flomax (tamsulosin), Rapaflo (silodosin), and Uroxatral (alfuzosin) are uroselective and are therefore associated with a lower risk of orthostatic hypotension. ○ The American Urological Association treatment guideline and a meta-analysis have indicated no differences in efficacy among doxazosin, tamsulosin, terazosin, and alfuzosin in the management of BPH (Djavan et al 1999, McVary et al 2011). ○ Silodosin was also shown to be similarly effective to tamsulosin in improving IPSS and LUTS secondary to BPH (Choo et al 2014, Cui et al 2012, Jung et al 2017, Miyakita et al 2010, Shirakawa et al 2013, Watanabe et al 2011). The 5-α-reductase inhibitors are FDA-approved for the management of BPH symptoms in men with an enlarged prostate and may be used to prevent clinical progression of BPH (McVary et al 2011). ○ Avodart (dutasteride) and Proscar (finasteride) are teratogenic and contraindicated in women. Therapy may increase the risk of high-grade prostatic cancer; therefore, evaluation for prostatic cancer should be performed prior to initiation of therapy and periodically during treatment. ○ Clinical trials have shown no significant differences between dutasteride and finasteride in reducing prostate volume and improving LUTS and maximum flow rate in men with BPH (Nickel et al 2011). ○ When compared to α1-adrenergic blocking agents, 5-α-reductase inhibitors were associated with a slower onset of improvement in BPH symptoms (Lee 2002). Combination therapy with an α1-adrenergic blocking agent and a 5-α-reductase inhibitor may be used in men with an enlarged prostate (McVary et al 2011). ○ In men with an enlarged prostate, combination therapy may lead to improved symptom control compared to monotherapy with either an α1-adrenergic blocker or a 5-α reductase inhibitor (Kaplan et al 2006). However, available data are inconsistent in this area, with another study demonstrating symptom control with combination therapy to be no better than with α1-adrenergic blocker monotherapy (Kirby et al 2003b). ○ Jalyn (dutasteride/tamsulosin) has been shown to reduce the risk of acute urinary retention or BPH-related surgery compared to tamsulosin monotherapy and watchful waiting (Becher et al 2009, Roehrborn et al 2015). Cialis (tadalafil), a PDE5 inhibitor, was approved by the FDA for the management of BPH. The American Urological Association treatment guideline currently does not have a recommendation for the place in therapy for PDE5 inhibitors (McVary et al 2011); however, the European Association of Urology treatment guideline suggests that PDE5 inhibitors are effective in patients with moderate-to-severe LUTS (Gravas et al 2017). ○ Cialis may cause hypotension and should not be administered within 48 hours of nitrate use. ○ Three meta-analyses and several other clinical studies have shown that Cialis was safe and effective in improving IPSS and LUTS secondary to BPH in men with or without concomitant erectile dysfunction (Broderick et al 2010, Dmochowski et al 2013, Donatucci et al 2011, Egerdie et al 2012, Gacci et al 2012, Gacci et al 2016, Goldfischer et al 2012, Oelke et al 2012, Porst et al 2011, Roehrborn et al 2008, Takahashi et al 2018, Wang et al 2018). Data as of February 13, 2018 SS-U/MG-U/ALS Page 7 of 10 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when
making medical decisions.
○ Combination therapy with the 5-α reductase inhibitor finasteride and Cialis was associated with modest improvements in urinary symptoms and significantly improved patient, but not clinician, global impression of improvement when compared with finasteride monotherapy (Casabe et al 2014). Guidance has been added to the Cialis prescribing information regarding dosing for this combination. Currently, Avodart, Cardura, Minipress, Flomax, Hytrin, Jalyn, Proscar, and Uroxatral are available generically. The brand product for Hytrin is no longer on the market; the product is only available generically.
REFERENCES Avodart [package insert], Research Triangle Park, NC: GlaxoSmithKline; September 2014. Becher E, Roehrborn CG, Siami P, et al; CombAT Study Group. The effects of dutasteride, tamsulosin, and the combination on storage and voiding in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the Combination of AVODART and Tamsulosin study. Prostate Cancer Prostatic Dis. 2009;12(4):369-74. Broderick GA, Brock GB, Roehrborn CG, et al. Effects of tadalafil on lower urinary tract symptoms secondary to benign prostatic hyperplasia in men with or without erectile dysfunction. Urology. 2010;75(6):1452-9. Cardura [package insert], New York, NY: Pfizer, Inc.; June 2016. Cardura XL [package insert], New York, NY: Pfizer, Inc.; February 2017. Casabe A, Roehrborn CG, Da Pozzo LF, et al. Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia. J Urol. 2014;191(3):727-33. Chang HS, Park CH, Kim DK, et al. Assessment of patient-reported outcome of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia and treated with tamsulosin HCl in Korea. Urology. 2010;75(5):1156-61. Choo MS, Song M, Kim JH, et al. Safety and efficacy of 8-mg once-daily vs 4-mg twice-daily silodosin in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (SILVER Study): a 12-week, double-blind, randomized, parallel, multicenter study. Urology. 2014;83(4):875- 81. Chung MS, Lee SH, Park KK, et al. Comparative rapid onset of efficacy between doxazosin gastrointestinal therapeutic system and tamsulosin in patients with lower urinary tract symptoms from benign prostatic hyperplasia: a multicenter, prospective, randomized study. Int J Clin Pract. 2011;65(11):1193-9. Cialis [package insert], Indianapolis, IN: Eli Lilly and Company; May 2017. Cui Y, Zong H, Zhang Y. The efficacy and safety of silodosin in treating BPH: A systematic review and meta-analysis. Int Urol Nephrol. 2012;44(6):1601-9. Cunningham GR, Kadmon D. Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia. UpToDate Web site. www.uptodate.com. Updated October 31, 2017[a]. Accessed February 12, 2018. Cunningham GR, Kadmon D. Epidemiology and pathogenesis of benign prostatic hyperplasia. UpToDate Web site. www.uptodate.com. Updated December 2017 [b]. Accessed February 12, 2018. Dahm P, Brasure M, MacDonald R, et al. Comparative effectiveness of newer medications for lower urinary tract symptoms attributed to benign prostatic hyperplasia: a systematic review and meta-analysis. Eur Urol. 2017;71:570-81. Demir O, Ozdemir I, Bozkurt O, et al. The effect of α-blocker therapy on erectile functions in patients with lower urinary tract symptoms due to benign prostate hyperplasia. Asian J Androl. 2009;11:716-22. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of α1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36(1):1-13. Dmochowski R, Roehrborn C, Klise S, et al. Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled 12-week clinical trial. J Urol. 2013;189:S135-S140. Donatucci CG, Brock GB, Goldfischer ER, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. Br J Urol. 2011;107:1110-6. Drugs@FDA: FDA approved drug products. Food and Drug Administration Web site. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed February 12, 2018. Egerdie RB, Auerbach S, Roehrborn CG, et al. Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study. J Sex Med. 2012;9(1):271-81. Filson CP, Hollingsworth JM, Clemens JQ, et al. The efficacy and safety of combined therapy with alphα-blockers and anticholinergics for men with benign prostatic hyperplasia: a meta-analysis. J Urol. 2013;190(6):2153-65. Flomax [package insert], Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; March 2017. Gacci M, Andersson KE, Chapple C, et al. Latest evidence on the use of phosphodiesterase type 5 inhibitors for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur Urol. 2016;70(1):124-133. doi: 10.1016/j.eururo.2015.12.048. Gacci M, Corona G, Salvi M, et al. A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α- blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol. 2012;61(5):994-1003. Goldfischer E, Kowalczyk J, Clark W, et al. Hemodynamic effects of once-daily tadalafil in men with signs and symptoms of benign prostatic hyperplasia on concomitant a1-adrenergic antagonist therapy: results of a multicenter randomized, double-blind, placebo-controlled trial. Urology. 2012;79(4):875-82. Gravas S, Bach T, Drake M, et al. Treatment of non-neurogenic male LUTS. European Association of Urology Web site. http://uroweb.org/guideline/treatment-of-non-neurogenic-male-luts/. 2017. Accessed February 12, 2018.
Data as of February 13, 2018 SS-U/MG-U/ALS Page 8 of 10 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when
making medical decisions.
Jalyn [package insert], Research Triangle Park, NC: GlaxoSmithKline; November 2017. Jun JEJ, Kinkade A, Tung ACH, Tejani AM. 5α- reductase inhibitors for treatment of benign prostatic hyperplasia: a systematic review and meta- analysis. Can J Hosp Pharm. 2017;70:113-9. Jung JH, Kim J, MacDonald R, et al. Silodosin for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia. Cochrane Database Syst Rev. 2017;11:CD012615. doi: 10.1002/14651858.CD012615.pub2. Kaplan SA, Lee JY, Meehan AG, et al; MTOPS Research Group. Long-term treatment with finasteride improves clinical progression of benign prostatic hyperplasia in men with an enlarged vs a smaller prostate: data from the MTOPS trial. J Urol. 2011;185(4):1369-73. Kaplan SA, McConnell JD, Roehrborn CG, et al. Combination therapy with doxazosin and finasteride for benign prostatic hyperplasia in patients with lower urinary tract symptoms and a baseline total prostate volume of 25 ml or greater. J Urol. 2006;175(1):217-20; discussion 220-1. Kaplan SA, Soldo KA, Olsson CA. Terazosin and doxazosin in normotensive men with symptomatic prostatism: a pilot study to determine the effect of dosing regimen on efficacy and safety. Eur Urol. 1995;28(3):223-8. Kaplan SA, Te AE, Ikeguchi E, et al. The treatment of benign prostatic hyperplasia with alpha blockers in men over the age of 80 years. Br J Urol. 1997;80(6):875-9. Karadag E, Oner S, Budak YU, et al. Randomized crossover comparison of tamsulosin and alfuzosin in patients with urinary disturbances caused by benign prostatic hyperplasia. In Urol Nephrol. 2011;43:949-54. Kawabe K, Yoshida M, Homma Y. Silodosin, a new alpha1A-adrenoceptor-selective antagonist for treating benign prostatic hyperplasia: results of a phase III randomized, placebo-controlled, double-blind study in Japanese men. BJU Int. 2006;98(5):1019-1024. Kirby RS, Andersen M, Gratzke P, et al. A combined analysis of double-blind trials of the efficacy and tolerability of doxazosin-gastrointestinal therapeutic system, doxazosin standard and placebo in patients with benign prostatic hyperplasia. BJU Int. 2001;87:192-200. Kirby RS. A randomized, double-blind crossover study of tamsulosin and controlled-release doxazosin in patients with benign prostatic hyperplasia. BJU Int. 2003[a];91(1):41-4. Kirby RS, Roehrborn C, Boyle P, et al. Efficacy and tolerability of doxazosin and finasteride, alone or in combination, in treatment of symptomatic benign prostatic hyperplasia: the prospective European doxazosin and combination therapy (PREDICT) trial. Urology. 2003[b];61(1):119-26. Kojima Y, Sasaki S, Imura M, et al. Tamsulosin reduces nighttime urine production in benign prostatic hyperplasia patients with nocturnal polyuria: a prospective open-label long-term study using frequency-volume chart. Neurourol Urodyn. 2012;31(1):80-5. Lapitan MCM, Acepcion V, Mangubat J. A comparative study on the safety and efficacy of tamsulosin and alfuzosin in the management of symptomatic benign prostatic hyperplasia: a randomized controlled clinical trial. J Int Med Res. 2005;33(5):562-73. Lee E. Comparison of tamsulosin and finasteride for lower urinary tract symptoms associated with benign prostatic hyperplasia in Korean patients. J Int Med Res. 2002;30(6):584-90. Leungwattanakij S, Watanachote D, Noppakulsatit P, et al. Sexuality and management of benign prostatic hyperplasia with alfuzosin: SAMBA Thailand. J Sex Med. 2010;7(9):3115-26. MacDonald R, Wilt TJ. Alfuzosin for treatment of lower urinary tract symptoms compatible with benign prostatic hyperplasia: a systematic review of efficacy and adverse effects. Urology. 2005;66(4):780-8.
Marks LS, Gittelman MC, Hill LA, et al. Rapid efficacy of the highly selective α1A-adrenoceptor antagonist silodosin in men with signs and symptoms of benign prostatic hyperplasia: pooled results of 2 phase 3 studies. J Urol. 2013;189:S122-S128. Matsukawa Y, Gotoh M, Komatsu T, et al. Efficacy of silodosin for relieving benign prostatic obstruction: prospective pressure flow study. J Urol. 2009;182:2831-5. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011;185(5):1793- 803. Minipress [package insert], New York, NY: Pfizer, Inc.; July 2016. Miyakita H, Yokoyama E, Onodera Y, et al. Short-term effects of crossover treatment with silodosin and tamsulosin hydrochloride for lower urinary tract symptoms associated with benign prostatic hyperplasia. Int J Urol. 2010;17:869-75. Na Y, Ye Z, Zhang S, et al; Chinese Dutasteride Phase III (ARIA108898) Trial Study Group. Efficacy and safety of dutasteride in Chinese adults with symptomatic benign prostatic hyperplasia: a randomized, double-blind, parallel-group, placebo-controlled study with an open-label extension. Clin Drug Investig. 2012;32(1):29-39. Nickel JC, Gilling P, Tammela TL, et al. Comparison of dutasteride and finasteride for treating benign prostatic hyperplasia: the enlarged prostate international comparator study (EPICS). BJU Int. 2011;108:388-94. Oelke M, Giuliano F, Mirone V, et al. Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomized, parallel, placebo-controlled clinical trial. Eur Urol. 2012;61:917-25. Orange Book: Approved drug products with therapeutic equivalence evaluations. Food and Drug Administration Web site. https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed February 12, 2018. Page ST, Hirano L, Gilchriest J, et al. Dutasteride reduces prostate size and prostate specific antigen in older hypogonadal men with benign prostatic hyperplasia undergoing testosterone replacement therapy. J Urol. 2011;186(1):191-7. Permpongkosol S, Krilad-O-Larn S, Ratana-O-Larn K. Treatment with a uroselective α1-blocker improves voiding and sexual function: a study in Thai men with lower urinary tract symptoms. J Sex Med. 2011;8(9):2582-9. Porst H, Kim ED, Casabe AR, et al. Efficacy and safety of tadalafil once daily in the treatment of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: results of an international randomized, double-blind, placebo-controlled trial. Eur Urol. 2011;60:1105-13. Proscar [package insert], Whitehouse Station, NJ: Merck& Co., Inc.; September 2013. Rahardjo D, Soebadi D, Sugandi S, et al. Efficacy and safety of tamsulosin hydrochloride compared to doxazosin in the treatment of Indonesian patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Int J Urol. 2006;13(11):1405-9. Rapaflo [package insert], Irvine, CA: Allergan USA, Inc.; June 2017. Ravish IR, Nerli RB, Amarkhed SS. Finasteride to evaluate the efficacy of dutasteride in the management of patients with lower urinary tract symptoms and enlarged prostate. Arch Androl. 2007;53(1):17-20. Ren RM, Kou M, Lan XX. Efficacy and safety of tamsulosin for the treatment of benign prostatic hyperplasia: a meta-analysis. Chin Med J (Engl). 2010;123(2):234-8.
Data as of February 13, 2018 SS-U/MG-U/ALS Page 9 of 10 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when
making medical decisions.
Roehrborn CG, Oyarzabal Perez I, et al. Efficacy and safety of a fixed-dose combination of dutasteride and tamsulosin treatment (Duodart ) compared with watchful waiting with initiation of tamsulosin therapy if symptoms do not improve, both provided with lifestyle advice, in the management of treatment-naive men with moderately symptomatic benign prostatic hyperplasia: 2-year CONDUCT study results. BJU Int. 2015;116(3):450-459. Roehrborn CG, McVary KT, Elion-Mboussa A, et al. Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: A dose finding study. J Urol. 2008;180(4):1228-34. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: four-year results from the CombAT study. Eur Urol. 2010;57:123-31. Samli MM, Dincel C. Terazosin and doxazosin in the treatment of BPH: results of a randomized study with crossover in non-responders. Urol Int. 2004;73(2):125-9. Shirakawa T, Haraguchi T, Shigemura K, et al. Silodosin versus naftopidil in Japanese patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized multicenter study. Int J Urol. 2013;20(9):903-10. Song K, Choo MS, Lee KS, et al. The long-term effect of alfuzosin in patients with lower urinary tract symptoms suggestive of benign prostate hyperplasia: evaluation of voiding and storage function with respect to bladder outlet obstruction grade and contractility. Urology. 2011;77:1177-82. Sun GH, Tsui KH, Wu TT, et al. Efficacy and safety of the doxazosin gastrointestinal therapeutic system for the treatment of benign prostate hyperplasia. Kaohsiung J Med Sci. 2010;26(10):532-9. Sun YH, Liu ZY, Zhang ZS, et al. Long-term efficacy and safety of tamsulosin hydrochloride for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia: data from China. Chin Med J (Engl). 2011;124(1):56-60. Tacklind J, Fink HA, Macdonald R, et al. Finasteride for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2010;(10):CD006015. doi: 10.1002/14651858.CD006015 Takahashi R, Miyazato M, Nishii, et al. Tadalafil improves symptoms, erectile function and quality of life in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (KYU-PRO Study). Low Urin Tract Symptoms. 2018;10(1):76-83. doi: 10.1111/luts.12143. Terazosin [package insert], Princeton, NJ: Sandoz, Inc.; July 2014. Toren P, Margel D, Kulkarni G, et al. Effect of dutasteride on clinical progression of benign prostatic hyperplasia in asymptomatic men with enlarged prostate: a post hoc analysis of the REDUCE study. BMJ. 2013;346:f2109 doi:10.1136/bmj.f2109. Tsai YS, Lan SK, Ou JH, et al. Effects of branded vs generic terazosin hydrochloride in adults with benign prostatic hyperplasia: a randomized, open- label, crossover study in Taiwan. Clin Ther. 2007;29(4):670-82. Uroxatral [package insert], St. Michael, Barbados: Concordia Pharmaceuticals, Inc.; August 2015. Wang Y, Bao Y, Liu J, et al. Tadalafil 5 mg once daily improves lower urinary tract symptoms and erectile dysfunction: a systematic review and meta- analysis. Low Urin Tract Symptoms. 2018;10(1):84-92. doi: 10.1111/luts.12144. Watanabe T, Ozono S, Kageyama S. A randomized crossover study comparing patient preference for tamsulosin and silodosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. J Int Med Res. 2011;39(1):129-42. Xue Z, Zhang Y, Ding Q, et al. Doxazosin gastrointestinal therapeutic system vs tamsulosin for the treatment of benign prostatic hyperplasia: a study in Chinese patients. Int J Urol. 2007;14(2):118-22. Yamanishi T, Mizuno T, Tatsumiya K, et al. Urodynamic effects of silodosin, a new a1A-adrenoceptor selective antagonist, for the treatment of benign prostatic hyperplasia. Neurourol Urodynam. 2010;29:558-62. Yin T, Qiao Z, Li Y, et al. Comparisons of the efficacy and safety of finasteride and dutasteride for benign prostatic hyperplasia: a network meta- analysis. Am J Ther. 2017;24:e517-23. Yokoyama T, Hara R, Fukumoto K, et al. Effects of three types of alpha-1 adrenoceptor blocker on lower urinary tract symptoms and sexual function in males with benign prostatic hyperplasia. Int J Urol. 2011;18:225-30. Zhang K, Yu W, Jin J, et al. Effect of doxazosin gastrointestinal therapeutic system 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms: a prospective, multicenter, randomized, open, parallel study. Urology. 2011;78:636-40.
Publication Date: March 26, 2018
Data as of February 13, 2018 SS-U/MG-U/ALS Page 10 of 10 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when
making medical decisions.